The goal of this CUTTING EDGE BASIC RESEARCH AWARD (CEBRA) application, submitted in response to PAR-09-222, is to determine the extent to which the G protein-coupled trace amine-associated receptor 1 (TAAR1) contributes to intravenous (i.v.) methamphetamine (METH) self-administration (SA). METH consumption is declining nation-wide yet significant use persists in specific demographics of the United States and around the world in spite of the overwhelmingly negative personal, familial, societal, and legal consequences associated with its use and abuse. For more than 50 years psychostimulant research has attempted to identify the biological substrates mediating METH's abuse potential. In spite of clarifying some of the biological mechanisms underlying METH's actions (e.g. interference with monoamine oxidase activity as well as dopamine, norepinephrine and vesicular monoamine transporter functions) there is still no widely accepted pharmacologic approach to medically managing the METH abstinence syndrome or preventing relapse to METH abuse. The lack of progress in this area suggests important biological molecules that contribute to METH's abuse liability other than enzymes and transporters remain to be discovered;a view supported by research involving genetically engineered mice. Recently we reported recombinant TAAR1, a G1s-coupled G protein-coupled receptor, is directly activated in vitro by nanomolar concentrations of METH to stimulate cAMP production. Furthermore, as no TAAR1 antagonist is commercially available we recently designed and synthesized a novel composition of matter, ET-92, that acts as a TAAR1-antagonist in vitro. These findings suggest to us TAAR1 might be a novel mediator of METH's actions in vivo and ET-92 could be a lead in developing a medication that interferes with behaviors relevant to METH abuse. However, an essential step in establishing the involvement of TAAR1 in METH abuse and the potential of ET-92 as an anti- METH lead compound is to evaluate them both in established animal models of drug taking behavior. We think our proposal is appropriate for the CEBRA mechanism because the hypothesis to be tested is unconventional: i.v. METH SA is mediated by TAAR1. To test our hypothesis we propose 2 specific aims: (1) Determine the extent to which TAAR1 mediates i.v. METH SA in adult wild type and TAAR1-deficient mice of both sexes and (2) Determine whether the novel TAAR1 antagonist ET-92 interferes with the acquisition, maintenance, extinction and/or reinstatement of i.v. METH SA in adult wild type mice of both sexes. We anticipate the successful completion of these aims will significantly influence the field of psychostimulant research by: (1) establishing a novel mechanism of METH's action that has long eluded the field and (2) by sparking interest in novel TAAR1-selective compounds as potential leads in the development of medications for preventing relapse to METH abuse in humans. PUBLIC HEALTH RELEVANCE: The abuse of methamphetamine (METH) has reached near epidemic proportions in many communities in the United States and its use continues to grow worldwide with devastating consequences for users, their families and society. Although behavioral modification strategies can prolong abstinence in some they do not prevent relapse to abuse in most individuals. At the present time no pharmacological treatment is available to prevent relapse to METH abuse. It is expected that the successful completion of the proposed research aims will result in a better understanding of the role the G protein-coupled trace amine-associated receptor 1 (TAAR1) plays in relapse to METH self- administration and in the process establish whether TAAR1 as an important new target for anti-METH medication development.